Effect of oral dosing vehicles on the acute hepatotoxicity of carbon tetrachloride in rats.
Although carbon tetrachloride (CCl4) is of concern as a drinking water contaminant, it has been necessary in most oral toxicity studies to give CCl4 in an oil vehicle due to its limited water solubility. The primary objective of our study was to assess the influence of dosing vehicles on the acute hepatotoxicity of CCl4. Fasted 200- to 230-g rats were generally found to be more susceptible to CCl4 hepatotoxicity than fasted 300- to 330-g rats. A time-course study revealed that corn oil did not delay the onset or time of maximal liver injury by an oral 100 mg/kg dose of CCl4, but did reduce the extent of injury relative to that when the chemical was given undiluted or as an aqueous emulsion. Fasted 200- to 230-g male Sprague-Dawley rats were given 0, 10, 25, 50, 100, 250, 500, or 1000 mg CCl4/kg body wt by gavage: in corn oil; as an aqueous emulsion; as the undiluted chemical; and in the 10 and 25 mg/kg doses only, in water. Blood and liver samples were taken 24 hr after dosing for measurement of serum and microsomal enzymes. Pathological examination of liver samples was also conducted. Dose-dependent increases in serum enzyme levels and pathological changes and dose-dependent decreases in microsomal P450 and glucose-6-phosphatase activity were observed in each vehicle group. Both the 10 and 25 mg/kg oral doses of CCl4 in water caused significant elevations in serum enzymes and hepatic centrolobular vacuolation. The study revealed that acute hepatotoxicity was less pronounced at each dosage level in rats given CCl4 in corn oil than in other vehicle groups. These findings demonstrate that dosing vehicles can significantly influence the acute hepatotoxicity of CCl4 in rats and are a cause for additional consideration and review of the practice of routinely using vegetable oils as a diluent in studies of volatile organic compound (VOC) toxicity. The use of aqueous Emulphor emulsions appears more appropriate in acute toxicity studies of VOC drinking water contaminants such as CCl4, in that the emulsion did not substantially alter the toxicity of CCl4 from that of undiluted CCl4 or CCl4 ingested in water.
Kim
H J
HJ
Department of Pharmacology and Toxicology, College of Pharmacy, University of Georgia, Athens 30602.
Odend'hal
S
S
Bruckner
J V
JV
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002251:Carbon Tetrachloride / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D003314:Corn Oil; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010938:Plant Oils; D051381:Rats; D011919:Rats, Inbred Strains; D012996:Solutions; D013997:Time Factors
D004337:Drug Carriers; D010938:Plant Oils; D012996:Solutions; D003314:Corn Oil; D002251:Carbon Tetrachloride